tbuckley/cabot-search huggingface dataset:
Moving the Needle to Reduce Acetaminophen (Paracetamol) Hepatotoxicity
Authors: Marc G. Ghany, Paul B. Watkins
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Ablation of p57+ Quiescent Cancer Stem Cells Suppresses Recurrence after Chemotherapy of Intestinal Tumors
Authors: Takeru Oka, Tsunaki Higa, Osamu Sugahara, Daisuke Koga, Shogo Nakayama, Keiichi I. Nakayama
Journal: Cancer Research (2023)

Abstract Quiescent cancer stem cells (CSC) are resistant to conventional anticancer treatments and have been shown to contribute to disease relapse after therapy in some cancer types. The identification and characterization of quiescent CSCs could facilitate the development of strategies to target this cell population and block recurrence. Here, we established a syngeneic orthotopic transplantation model in mice based on intestinal cancer organoids to profile quiescent CSCs. Single-cell transcriptomic analysis of the primary tumors formed in vivo revealed that conventional Lgr5high intestinal CSCs comprise both actively and slowly cycling subpopulations, the latter of which specifically expresses the cyclin-dependent kinase inhibitor p57. Tumorigenicity assays and lineage tracing experiments showed that the quiescent p57+ CSCs contribute in only a limited manner to steady-state tumor growth but they are chemotherapy resistant and drive posttherapeutic cancer recurrence. Ablation of p57+ CSCs suppressed intestinal tumor regrowth after chemotherapy. Together, these results shed light on the heterogeneity of intestinal CSCs and reveal p57+ CSCs as a promising therapeutic target for malignant intestinal cancer. Significance: A quiescent p57+ subpopulation of intestinal CSCs is resistant to chemotherapy and can be targeted to effectively suppress the recurrence of intestinal cancer.
Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function
Authors: Marion Laudette, Malin Lindbom, Muhammad Arif, Mathieu Cinato, Mario Ruiz, Stephen Doran, Azra Miljanovic, Mikael Rutberg, Linda Andersson, Martina Klevstig, Marcus Henricsson, Per-Olof Bergh, Entela Bollano, Nay Aung, J Gustav Smith, Marc Pilon, Tuulia Hyötyläinen, Matej Orešič, Rosie Perkins, Adil Mardinoglu, Malin C Levin, Jan Borén
Journal: Cardiovascular Research (2023)

Abstract Aims Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9−/− mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. Methods and results Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9−/− mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9−/− hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9−/− mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9−/− mice. Circulating lipid levels were unchanged in CM-Pcsk9−/− mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9−/− mice had an increased number of mitochondria–endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. Conclusion PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.
Bacterial flagellin is a dominant, stable innate immune activator in the gastrointestinal contents of mice and rats
Authors: Matam Vijay-Kumar, Venugopal R. Bovilla, Beng San Yeoh, Rachel M. Golonka, Piu Saha, Bina Joe, Andrew T. Gewirtz
Journal: Gut Microbes (2023)

Intestinal contents comprise the largest repository of immunogenic ligands of microbial origin. We undertook this study to assess the predominant microbe-associated molecular patterns (MAMPs) present therein and the receptors) that mediate the innate immune responses to them. Here, we demonstrated that intestinal contents from conventional, but not germ-free, mice and rats triggered robust innate immune responses in vitro and in vivo. Such immune responses were abrogated in the absence of either myeloid differentiation factor 88 (MyD88) or Toll-like receptor (TLR) 5, but not TLR4, suggesting that the stimuli was flagellin (i.e., protein subunit of flagella that drives bacterial motility). Accordingly, pre-treating intestinal extracts with proteinase, thereby degrading flagellin, was sufficient to block their ability to activate innate immune responses. Taken together, this work serves to underscore flagellin as a major, heat-stable and bioactive MAMP in the intestinal content that confers this milieu strong potential to trigger innate immune responses.
Bone‐Targeted Exosomes: Strategies and Applications
Authors: Jian Wang, Xiaoqun Li, Sicheng Wang, Jin Cui, Xiaoxiang Ren, Jiacan Su
Journal: Advanced Healthcare Materials (2023)

Abstract As the global population ages, bone‐related diseases have increasingly become a major social problem threatening human health. Exosomes, as natural cell products, have been used to treat bone‐related diseases due to their superior biocompatibility, biological barrier penetration, and therapeutic effects. Moreover, the modified exosomes exhibit strong bone‐targeting capabilities that may improve efficacy and avoid systemic side effects, demonstrating promising translational potential. However, a review of bone‐targeted exosomes is still lacking. Thus, the recently developed exosomes for bone‐targeting applications in this review are focused. The biogenesis and bone‐targeting regulatory functions of exosomes, the constructive strategies of modified exosomes to improve bone‐targeting, and their therapeutic effects for bone‐related diseases are introduced. By summarizing developments and challenges in bone‐targeted exosomes, It is striven to shed light on the selection of exosome constructive strategies for different bone diseases and highlight their translational potential for future clinical orthopedics.
Conditioning therapy with <scp>N‐acetyl‐L</scp>‐cysteine, decitabine and modified <scp>BUCY</scp> regimen for myeloid malignancies patients prior to allogeneic hematopoietic stem cell transplantation
Authors: Yaqiong Tang, Ziyan Zhang, Silu Liu, Yifang Yao, Tingting Pan, Jiaqian Qi, Huizhu Kang, Yuejun Liu, Chengsen Cai, Meng Zhou, Xuefeng He, Xiaohui Hu, Xiao Ma, Depei Wu, Yue Han
Journal: American Journal of Hematology (2023)

Conditioning therapy is an essential procedure prior to hematopoietic stem cell transplant (HSCT), imposing a great impact on the outcomes of recipients. We performed a prospective randomized controlled trial to assess the outcome of HSCT recipients with myeloid malignancies after receiving the conditioning therapy consisting of modified BUCY (mBUCY), N-acetyl-L-cysteine (NAC), and decitabine. Enrolled patients were randomly allocated to either Arm A (decitabine, day -12 to -10; NAC, day -9 to +30; mBUCY, day -9 to -2), or Arm B (mBUCY regimen followed by stem cells infusion). Seventy-six patients in Arm A and 78 patients in Arm B were finally evaluated. The results showed platelet recovery accelerate in Arm A, with more patients achieving a platelet count of ≥50 × 109 /L than Arm B at day +30 and +60 (p = .004 and .043, respectively). The cumulative incidence of relapse is 11.8% (95% CI 0.06-0.22) in Arm A, and 24.4% (95% CI 0.16-0.35) in Arm B (p = .048). The estimated 3-year overall survival rate was 86.4% (±4.4%) and 79.9% (±4.7%) in 2 arms, respectively (p = .155). EFS at 3 years was 79.2% (±4.9%) in Arm A and 60.0% (±5.9%) in Arm B (p = .007). Intracellular reactive oxygen species (ROS) level was found to be reversely correlated with platelet recovery, and fewer patients in Arm A displayed excessive ROS within hematopoietic progenitor cells compared to Arm B. In conclusion, the addition of decitabine and NAC to mBUCY is a feasible and promising conditioning therapy for myeloid malignancies patients.
The Tumor Suppressor Functions of Ubiquitin Ligase KPC1: From Cell-Cycle Control to NF-κB Regulator
Authors: Diana Gulei, Rares Drula, Gabriel Ghiaur, Anca Dana Buzoianu, Yelena Kravtsova-Ivantsiv, Ciprian Tomuleasa, Aaron Ciechanover
Journal: Cancer Research (2023)

Abstract The ubiquitin-proteasome system (UPS) is responsible for up to 90% of intracellular protein degradation. Alterations in UPS are extensively involved in the development and advancement of malignant pathologies. Thus, the components of the UPS can become potential targets for cancer therapeutics. KPC1 is an E3 ubiquitin ligase component of the UPS that regulates key pathways and processes in cancer. KPC1 sustains the ubiquitination of cytoplasmic p27, determining its elimination and transition between cell-cycle phases. KPC1 also regulates NF-κB signaling by inducing ubiquitination of p105 to allow subsequent proteasomal processing to the functional form p50. It has been shown that the KPC1-p50 duo is reduced or absent in multiple malignancies and that therapeutic reinforcement of the functional axis can exhibit significant tumor suppressor activity. Here, we highlight the potential role of KPC1 as a tumor suppressor by fully describing its crucial role in p27 signaling and the canonical NF-κB pathway.
68Ga-FAPI04 Versus 68Ga-DOTATATE PET/CT in a Patient With Multiple Meningioma
Authors: Dilara Denizmen, Emine Goknur Isik, Fikret Buyukkaya, Serkan Kuyumcu
Journal: Clinical Nuclear Medicine (2023)

Abstract We present the 68 Ga-DOTATATE and 68 Ga-FAPI (fibroblast activation protein inhibitor) PET/CT findings of a 61-year-old man diagnosed with atypical World Health Organization grade II multiple meningiomas. The patient has been stable for 2 years following multiple surgeries and external radiotherapy because of recurring disease until he recently described frequent headaches, and a follow-up examination confirmed new meningioma lesions on MRI. However, the patient was inoperable and was referred for 68 Ga-DOTATATE PET/CT to determine eligibility for salvage peptide receptor radionuclide therapy. He also underwent fibroblast activation protein–targeted imaging using 68 Ga-FAPI04 PET/CT, which revealed heterogeneous, low to mild fibroblast activation protein expression across multiple meningioma lesions.
Unintended Pregnancy and Maternal and Infant Health Outcomes—Reply
Authors: Heidi D. Nelson, Katherine Ahrens, Rongwei Fu
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Increased Petrous Bone Uptake on 18F-PSMA-1007 PET/CT Due to Otospongiosis
Authors: Sophie Neveü, Minerva Becker, Nils Guinand, Ismini Charis Mainta, Vincent Lenoir
Journal: Clinical Nuclear Medicine (2023)

We report the case of a 74-year-old man who had undergone radical prostatectomy for prostatic cancer 6 months earlier. Elevated prostate-specific antigen during follow-up prompted 18 F-prostate-specific membrane antigen (PSMA) ligand PET/CT ( 18 F-PSMA-1007 PET/CT) to search for new manifestations of prostate cancer, revealing an increased focal uptake (SUV max , 5.9) in the left cochlear/pericochlear temporal bone and equivocal PSMA-RADS-3a external iliac nodes. Comparison with cone-beam CT and MRI showed that the focal temporal bone uptake corresponded to the typical morphological features of active otospongiosis (otosclerosis) in the context of a previously known long-standing otospongiosis.
Opioid death projections with AI-based forecasts using social media language
Authors: Matthew Matero, Salvatore Giorgi, Brenda Curtis, Lyle H. Ungar, H. Andrew Schwartz
Journal: npj Digital Medicine (2023)

Targeting of location-specific aid for the U.S. opioid epidemic is difficult due to our inability to accurately predict changes in opioid mortality across heterogeneous communities. AI-based language analyses, having recently shown promise in cross-sectional (between-community) well-being assessments, may offer a way to more accurately longitudinally predict community-level overdose mortality. Here, we develop and evaluate, TROP (Transformer for Opiod Prediction), a model for community-specific trend projection that uses community-specific social media language along with past opioid-related mortality data to predict future changes in opioid-related deaths. TOP builds on recent advances in sequence modeling, namely transformer networks, to use changes in yearly language on Twitter and past mortality to project the following year's mortality rates by county. Trained over five years and evaluated over the next two years TROP demonstrated state-of-the-art accuracy in predicting future county-specific opioid trends. A model built using linear auto-regression and traditional socioeconomic data gave 7% error (MAPE) or within 2.93 deaths per 100,000 people on average; our proposed architecture was able to forecast yearly death rates with less than half that error: 3% MAPE and within 1.15 per 100,000 people.
Coinheritance of PIEZO1 variants and multi‐locus red blood cell defects account for the symptomatic phenotype in beta‐thalassemia carriers
Authors: Valeria Maria Pinto, Roberta Russo, Sabrina Quintino, Barbara Eleni Rosato, Roberta Marra, Federica Del Giudice, Massimo Mogni, Massimo Maffei, Achille Iolascon, Gian Luca Forni, Immacolata Andolfo
Journal: American Journal of Hematology (2023)

Workflow of the study with some examples of the achieved results.
Human small intestine contains 2 functionally distinct regulatory T-cell subsets
Authors: Sudhir Kumar Chauhan, Raquel Bartolomé Casado, Ole J.B. Landsverk, Hanna Johannessen, Danh Phung, Hogne Røed Nilsen, Frank Sætre, Jørgen Jahnsen, Rune Horneland, Sheraz Yaqub, Einar Martin Aandahl, Knut E.A. Lundin, Espen S. Bækkevold, Frode L. Jahnsen
Journal: Journal of Allergy and Clinical Immunology (2023)

Regulatory T (Treg) CD4 cells in mouse gut are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and members of the microbiota. However, information about the phenotype and function of Treg cells in the human gut is limited.
CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma
Authors: Marc Gauthier, Sagar Laxman Kale, Timothy B. Oriss, Michael Gorry, Richard P. Ramonell, Kathryn Dalton, Prabir Ray, John V. Fahy, Max A. Seibold, Mario Castro, Nizar Jarjour, Benjamin Gaston, Eugene R. Bleecker, Deborah A. Meyers, Wendy Moore, Annette T. Hastie, Elliot Israel, Bruce D. Levy, David Mauger, Serpil Erzurum, Suzy A. Comhair, Sally E. Wenzel, Anuradha Ray
Journal: Journal of Allergy and Clinical Immunology (2023)
Molecular mechanisms of ferroptosis and their involvement in brain diseases
Authors: Inês Costa, Daniel José Barbosa, Sofia Benfeito, Vera Silva, Daniel Chavarria, Fernanda Borges, Fernando Remião, Renata Silva
Journal: Pharmacology & Therapeutics (2023)

Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.
Effects of repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex on symptom domains in neuropsychiatric disorders: a systematic review and cross-diagnostic meta-analysis
Authors: Rebecca L D Kan, Frank Padberg, Cristian G Giron, Tim T Z Lin, Bella B B Zhang, Andre R Brunoni, Georg S Kranz
Journal: The Lancet Psychiatry (2023)
Mpox respiratory transmission: the state of the evidence
Authors: Amy Beeson, Ashley Styczynski, Christina L Hutson, Florence Whitehill, Kristina M Angelo, Faisal S Minhaj, Clint Morgan, Kaitlyn Ciampaglio, Mary G Reynolds, Andrea M McCollum, Sarah Anne J Guagliardo
Journal: The Lancet Microbe (2023)

The relative contribution of the respiratory route to transmission of mpox (formerly known as monkeypox) is unclear. We review the evidence for respiratory transmission of monkeypox virus (MPXV), examining key works from animal models, human outbreaks and case reports, and environmental studies. Laboratory experiments have initiated MPXV infection in animals via respiratory routes. Some animal-to-animal respiratory transmission has been shown in controlled studies, and environmental sampling studies have detected airborne MPXV. Reports from real-life outbreaks demonstrate that transmission is associated with close contact, and although it is difficult to infer the route of MPXV acquisition in individual case reports, so far respiratory transmission has not been specifically implicated. Based on the available evidence, the likelihood of human-to-human MPXV respiratory transmission appears to be low; however, studies should continue to assess this possibility.